Acetals and ketals of 16, 17-dihydroxy steroids



United States Patent Josef Fried, Princeton, NJ, assignor to 01in Mathieson Chemical (lorporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Apr. 25, 1960, Ser. No. 24,230 37 Claims. (Cl. 260-23955) This application is a continuation-in-part of my applications: Serial No. 677,205, filed August 9, 1957, now abandoned; Serial No. 707,463, filed l'anuary 7, 1958, now Patent No. 2,975,172, granted March 14, 1961; Serial No. 714,047, filed February 10, 1958, now abandoned; Serial No. 714,076, filed February 10, 1958, now abandoned; Serial No. 718,966, filed March 4, 1958, now abandoned; Serial No. 772,404, filed November 7, 1958, which in turn is a continuation-in-part of said Serial No. 677,205, and Serial No. 719,504, filed March 6, 1958, now abandoned; Serial No. 772,405, filed November 7, 1958, now abandoned; and Serial No. 797,867, filed March 9, 1959, now abandoned.

T his invention relates to, and has for its object the provision of a method of preparing physiologically active steroids, and to the physiologically active steroids produced thereby.

It has unexpectedly been found that when a steroid of the 16a,17ot-dihydroxy 3,20-diketo-A -pregnene series containing either a fi-hydroxy or keto group in the ll-position is ketalized or acetalized by reaction with a ketone or an aldehyde of at least two carbon atoms, thereby forming the corresponding 16,17-cyclic ketal or acetal derivative, the physiological activity of the starting steroid is increased. This discovery is surprising since a priori it would have been thought that such a treatment would either destroy the activity, or at best, because of in vivo hydrolysis, yield a compound no more active than the starting steroidal substance.

In its broadest aspects, therefore, this invention relates to the discovery that the physiological activity of a 16cc,- 17a-dihydroxy3,20-diketo steroid of the M-pregnene series (including the pregnadiene and pregnatriene series) having either an 11 fi-hydroxy or ll-keto group can be increased by forming a 16,17-cyclic acetal or ketal derivative thereof with an aldehyde of at least two carbon atoms or a ketone.

Although any such steroid can be treated in accordance with the process of this invention to yield the new 16,17-cyclic acetal and ketal derivatives of this invention,

the prefererd compounds of this invention are those of the general formula wherein the 1,2 and 6,7-positions are saturated or doublebonded; R is hydrogen, R is hydroxy or a-acyloxy, or together R and R is keto; each X is hydrogen, halogen, hydroxy, lower alkoxy, or lower alkyl, at least one X being hydrogen; Y and Y are hydrogen or methyl; Z is hydrogen, halogen, hydroxy or acyloXy; P is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo 3,048,581 Patented Aug. 7, 1962 lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower 'alkyl or together with the carbon atom to which they are joined P and Q are cycloalkyl or monocyclic heterocyclic. Particularly preferred are those compounds wherein the 1,2-position is double-bonded, R is hydrogen, R is B-hydroxy or together R and R is keto; X is halogen (optimally fiuoro), Y and Y are hydrogen; Z is hydroxy or acyloxy; and P and Q are each lower alkyl.

The compounds of this invention are prepared by interacting a 16a,17u-dihydroxy-3,20-diketo steroid of the A pregnene series, having either an llfi-hydrony or ll-keto group, with an aldehyde of at least two carbon atoms or ketone. The reaction is preferably carried out by treating a suspension or solution of the steroid in the aldehyde or ketone (or an organic solvent if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid, and hydrochloric acid), neutralizing the acid and recovering the cyclic acetal or ketal derivative formed.

Particularly preferred as starting those of the general formula steroidal materials are wherein the 1,2 and 6,7-positions are saturated or doublebonded, R, R, X, Y and Y are as hereinbefore defined, and Z is hydrogen, halogen or hydroxy. Particularly preferred carbonyl reactants are those of the general formula:

wherein P and Q are as hereinbefore defined.

Among the suitable starting steroids utilizable in the process of this invention may be mentioned:

16a-hydroxyhydrocortisone, 16ot-hydroxycortisone, 16ot-hydroxyprednisolone, l6a-hydroxyprednisone, Qa-halo-16a-hydroxyhydrocortisones (i.e., 9ot-fluoro-l6oshydroxyhydrocortisone, 9a-chloro16a-hydroxyhydrocortisone, 9a-bromo-16u-hydroxyhydrocortisone and 9aiodo-16ahydroxyhydrocortisone) 9a-halo-16ot-hydroxycortisones, 9u-ha1o-l6u-hydroxyprednisolone (e.g. 9a-halo-16ot-hydroxyprednisones, 12ec-halo-l6ot-hydroxyhydrocortisones (erg. 12a-fiuoro- 16a-hydroxyhydro cortisone) 12ot-halo-16a-hydroxycortisones (cg. 12tx-chloro-16ahydroxycortisone) 12a-halo-16a-hydroxyprednisolones (e.g. 12a-fl11OI0'l6oahydroxyprednisolone) 12a-halo-16u-hydroxyprednisones, 6a-methyl-16a-hydroxyhydrocortisone, 6a-methyl-16a-hydroxycortisone, 6zx-methyl-16u-hydroxyprednisolone, 6tx-rnethyl-16a-hydroxyprednisone, 2a-methyl-l 6ahydroxyhydrocortisone, Zu'methyl-16othydroxycortisone,

, triamcinolone) monocyclic heterocyclic lower alkanones; and oxo lower alkanoic acids such as glyoxylic, pyruvic, acetoacetic, fi-ketopropionic, a-ketobutyric, levulinic, fi-keto-caproic and B-ketocaprylic acid [as well as salts and esters thereof, such as the lower alkyl esters (e.g. methyl and ethyl)].

If a keto acid is employed as the acetalizing or ketalizing agent, although the free acid may be used as such, thereby directly yielding the free acid derivative, a preferred method for forming these derivatives is by an initial reaction with an ester of the desired ketoacid and subsequent hydrolysis of the ester derivative, as by treatment with a dilute mineral acid, to yield the free acid derivative. The free acid can then, if desired, be neutralized with any desired base (preferably ammonium hydroxide or an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide), to yield the salt derivative, or esterified by reaction with the desired alcohol (preferably a lower alkanal, such as methanol), in the usual manner, to yield an ester derivative, which diifers from the initial ester reactant.

If a 21-ester derivative is the desired product, the corresponding Zl-hydroxy steroid can be acylated in the usual manner. Thus, to prepare the Zl-acyloxy derivatives wherein the acyl radical corresponds to the acyl radical of a hydrocarbon monocarboxylic acid of less than ten carbon atoms, either the acyl halide or acid anhydride of a lower alkanoic acid (e.g. acetic, propionic and tert-pentanoic acid), a monocyclic aryl carboxylic acid (cg. benzoic and toluic acid) a monocyclic aryl lower alkanoic acid (e.g. phenacetic and fi-phenylpropionic acid), a lower alkenoic acid, a cycloalkane carboxylic acid, or a cycloalkene carboxylic acid is employed as a reactant.

To prepare the 2l-acyloxy derivatives wherein the acyl radical corresponds to the acyl radical of a hydrocarbon dicarboxylic acid of less than twelve carbon atoms either the acid anhydride or acyl halide (preferably acyl chloride) of a hydrocarbon dicarboxylic acid of less than twelve carbon atoms is used. Suitable hydrocarbon dicarboxylic acids include the lower alkanedioic acids (eg. oxalic, malonic, succinic, glutaric, adipic, pimelic, suber-ic, azelaic, and sebacic acid), lower alkenedioic acids (e.g. maleic, fumaric, and citraconic acid), cycloalkanedioic acids, cycloalkenedioic acids, and monocyclic aromatic dicarboxylic acids (e.g. the phthalic acids). The preferred reactants are the inner anhydrides of lower alkanedioic acids having four to five carbon atoms (i.e. succinic anhydride and glutaric anhydride) and the anhydrides of the phthalic acids, and the esterification reaction is preferably conducted in the presence of an organic base (e.g. pyridine) at an elevated temperature. To prepare the watersoluble salts the 21-ester thus formed (containing a free carboxy group) is reacted either in situ or in a separate step with a base. Suitable bases include: inorganic bases, such as ammonium hydroxide, the alkali metal hydroxides (e.g. potassium hydroxide and sodium hydroxide), and the alkaline earth metal hydroxides; and organic bases, such as di(lower alkyl) amines and heterocyclic amines (e.g. pyridine). The alkali metal hydroxides are preferred.

To prepare the 21-phosphate derivatives, the 21-hydroxy steroid is reacted with an excess of phosphorous oxy chloride, and the resulting dichloride hydrolyzed by treatment with water in the presence of an organic base, such as pyridine.

Those compounds of this invention having a halogen in the 2l-position can be prepared directly by employing as a starting steroid a compound containing the desired 21- halo group. However, the 2l-halo final products are preferably prepared from the corresponding 21-hydroxy steroid derivative by reacting the latter with an alkane or aryl sulfonyl halide (sulfonyl chlorides being preferred, although other halides such as bromides and iodides may be used) to yield the new 21-alkane (or aryl) sulfonyloxy intermediates of this invention. Although any alkane (or aryl) sulfonyl chloride may be used, the alkane group is preferably a lower alkane, methanesulfonyl chloride (mesyl chloride) being particularly preferred, and the aryl group is preferably p-tolyl. The reaction is carried out by intermixing the 2l-hydroxy steroid and sulfonyl halide under substantially anhydrous conditions and preferably in the cold (e.g. a temperature less than about 20 C.), in the presence of pyridine or other organic tertiary base.

The reaction results in the preparation of the new 21- alkane (or aryl) sulfonyloxy compounds of this invention, particularly steroids of the following general formula wherein tle 1,2 and 6,7-positions are saturated or double-bonded: R, R, X, Y, Y, P and Q are as hereinbefore defined, and R is preferably lower alkyl or tolyl.

These 2l--alkane (or aryl) sulfonyloxy intermediates are then reacted with a metal halide (such as an alkali metal halide, particularly potassium billuoride, potassium fluoride, lithium chloride, lithium bromide and sodium iodide) in an organic solvent. The reaction is conducted at an elevated temperature (eg. at reflux), under substantially neutral conditions. The reaction results in the roduction of new 2l-halo steroids of this invention having the general formula wherein the 1,2 and 6,7-positions are saturated or doublebonded; and R, R, X, Y, Y, P and Q are as hereinbefore defined. To prepare those compounds which represent a bis-steroidal compound joined together through the respective 21-groups, that is steroids of the general formula wherein the 1,2 and 6,7-positions are saturated or doublebonded; and R, R, X, Y, Y, P and Q are as hereinbefore defined, and T is a divalent radical, such as an inorganic radical (e.g. -SO- and SO an an organic radical [c.g. -CO- and PO(R), wherein R" is an organic radical such as phenyl], a steriod of the general formula wherein the 1,2 and 6,7-positions are saturated or doublebonded, and R, R, X, Y, Y, P and Q are as hereinbefore defined, is reacted with a compound of the formula T(halo) wherein the halo is preferably chloro. The reaction is preferably conducted in the presence of an organic base, such as pyridine, in the cold (i.e., below ambient temperature). Suitable reactants include thionyl chloride, sulfuryl chloride, phosgene and phenylphosphonyl dichloride.

All of the compounds of this invention are physiologically active substances which possess glucocorticoid and anti-inflammatory activity and hence can be used in lieu of known glucocorticoids such as hydrocortisone and cortisone in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same manner as hydrocortisone, forexample, the dosage being adjusted for the relative potency of the particular steroid. In addition, all of the compounds of this invention can be used topically in lieu of known glucocorticoids such as hydrocortisone in the treatment of skin conditions such as dermatitis, sunburn, neurodermatitis, eczema, and anogenital pruritus. The water-soluble salts of this invention, in contrast to the parent free 21-hydroxy steroid or the monobasic esters thereof, are particularly well suited fortopic'al administration, especially for use in otic and ophthalmic preparations.

In those cases wherein the starting steroid reactants are new compounds, they can be prepared from the corresponding l6-desoxy derivative by subjecting the latter to the oxygenating action of a microorganism such as Streptomyces roseochromogenus in accordance with the method described in US. Patent No. 2,855,343. The 9a-halo- 11,8,16a,17u-trihydroxyprogesterone starting materials can be prepared as disclosed in my application, Serial No. 707,463, filed January 7, 1958, now Patent No. 2,975,172, granted March 14, 1961.

The following examples specifically disclose methods for preparing representative 16u,17a-dihydroxy starting steroidal materials. Neither these methods nor the compounds'prepared constitute an aspect of the instant invention, but rather in certain instances these compounds and/ or their method of preparation are separately claimed in appplications wherein I am the sole or joint inventor.

In the following examples all temperatures are in centigrade:

EXAMPLE A 16a-Hydr0'xyprednisol0'ne (a) Preparation of 12a-fluoro-11,8,16a-dihydroxypr0- gesterone: Microbiological hydroxylation of 12a-fluoro llfi-hydroxyprogesterone with Streptomyces roseochro- '7 ture is allowed to stand in the dark 8 mogenus (Waksman No. 3689) as described in Example 11 of Patent No. 2,855,343 produces 160L-hydl'0XY-120tfluoro-1 lB-hydroxyprogesterone.

(b) Preparation of 12a-lluoro-A -pregnadiene-1118-01- 3,20-dione: A suspension of 400 mg. of 16a-hydroxy-12afiuoro-llp-hydroxyprogesterone and 1.2 g. of aluminum tertiary butylate in 120 ml. of anhydrous toluene is heated to reflux for 2 hours. The cooled reaction mixture is washed with dilute hydrochloric acid, water, bicarbonate and again with water until neutral. The organic phase is dried over sodium sulfate and the solvent removed in vacuo. The residual crystalline mass upon recrystallization from acetone-hexane furnishes pure 12a-fluoro-A pregnadiene-l 1,8-ol-3,20-dione.

(0) Preparation of IZwfiuOro-M- regnene-I1 3,16a,17atriol-3,20-dione: To a solution of 77 mg. of the diene formed in section (b) and 0.1 ml. of pyridine in 5 ml. of benzene is added 65 mg. of osmium tetroxide. The mixture is allowed to stand in the dark for 18 hours, after which period precipitation of a brown crystalline material occurs. For decomposition of the osmate ester there is added to the mixture 7 ml. of water, 4.6 ml. of methanol, 700 mg. of sodium sulfite and 700 mg. of potassium bicarbonate and the resulting suspension is stirred for four hours at room temperature. After dilution with 20 ml. of chloroform the mixture is filtered through Celite and the precipitate washed thoroughly with chloroform. The layers are separated, the chloroform phase washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue is recrystallized from acetone-hexane, leaving the pure triol of the following properties: M. P. about 220222 [a] |102 (c., 0.38 in CHCl x 33, 240 m, (e=16,200), 2.90, 5.83, 6.02, 6.19,.

Analysis-Calm. for C H O |F (380.44): C, 66.29; H, 7.68. Found: C, 66.28; H, 7.67.

By applying the same sequence of reactions 'to fluoro llfl-hydroxyprogesterone, 9ot-fiuoro-A -preg'nane- 1 113,16a,l7oz-tIlOl-3,2Q-dl0l1 is formed.

EXAMPLE C 12a-Methyl-A -Pregnane-I1,8,1 6a,] 7 a-T rial-3,20-Di0ne (a) Preparation of 12a-methyl-11,8,16a-dihydroxyprogesterone: Microbiological hydroxylation of 12a-methylllfl-hydroxyprogesterone with Streptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,855,343 produces 16a-hydroxy-12ot-methyl-1 lfi-hydroxyprogesterone.

(b) Preparation of 12a-methyl-A -pregnadiene-11pol-3,20-'dione: A suspension of 400 mg. of 16ot-hydroxy- IZa-methyl-l l'fl-hydroxyprogesterone and 1.2 g. of aluminum tertiary butylate in ml. of anhydrous toluene is heated to reflux for 2 hours. The cooled reaction 'mixture is washed with dilute hydrochloride acid, water, b-icarbonate and again with water until neutral. The organic phase is dried over sodium sulfate and the solvent removed in vacuo. The residual crystalline mass upon recrystallization from acetone-hexane furnishes pure 12amethyl-A -pregnadiene-1 1 3-ol-3,20-dione.

(c) Preparation of 12u-methyl-A -pregnene-11,6,16a, l7a-triol-3,20-dione: To a solution of 77 mg. of the diene formed in section (b) and 0.1 ml. of pyridine in 5 ml. of benzene is added 65 mg. of osmium tetroxide. The mixfor 18 hours during which period precipitation of a brown crystalline material occurs. For decomposition of the osmate ester there is added to the mixture 7 ml. of water, 4.6 ml. of methanol, 700 mg. of sodium sulfite and 700 mg. of potassium bicarbonate and the resulting suspension is stirred for four hours at room temperature. After dilution with 20 ml. of chloroform the mixture is filtered through Celite and the precipitate washed thoroughly with chloroform. The layers are separated, the chloroform phase washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue is recrystallized from acetone-hexane, leaving the pure triol.

By applying the same sequence of reactions to 9a-methyl-l 1 ,B-hydroxyprogesterone, 9u-methyl-A -pregnene-116, 16cc,17ot't11013,20-di0116 is prepared.

EXAMPLE D 1 2a-Chl0r0-1 6a-Hydr0xyc0rtis0ne Microbiological hydroxylation of IZzx-ChlOIOCOItiSOHfi with Streptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,855,343 produces 120:- chloro-16othydroxycortisone.

EXAMPLE E 12ot-Flll07O-1 6 a-H ydroxylzydrocartisone Microbiological hydroxylation of 12a-fiuoro-hydrocortisone with Streptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,855,343 furnishes 12a-flu0ro-16oc-hydroxyhydrocortisone.

EXAMPLE F 12 aFlLlr0-l wHy a'roxyprednisolone Microbiological hydroxylation of l2a-fiuoro-prednisolone with S treptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,855,343 furnishes 12afluoro-16a-hydroxy-prednisolone.

EXAMPLE G 6 Ot-M 3th [-1 6ot-Hydroxyprednisolone Microbiological hydroxylation of 6ot-methyl prednisolone with Streptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,855,343 furnishes 60cmethyl- 1 6a-hydroxyprednisolone.

EXAMPLE H 9u-Fluoro-6zx-Methy l-] 6 a-H ydroxy predrzisolone Microbiological hydroxylation of 9ot-fluoro-6u-methyl prednisolone with Streptomyces roseochromogenus (Waksman No. 3689) as described in Patent No. 2,885,- 343 furnishes 9u-fiuoro-6a-methyl-16a-hydroxyprednisolone.

The following examples are illustrative of the preparation of those compounds of this invention wherein the 21- position is unsubstituted or contains a hydroxyl group (Z is hydrogen or hydroxy). 1n the examples, the products are named either with a prefix or sufiix to indicate the acetal or ketal group. Thus, the reaction product of triamcinolone with acetone is sometimes named 16,17-isopropylidene triamcinolone and other times triamcinolone acetonide. Moreover, in those instances where the correct chemical name would be cumbersome, a shortened name is used. Thus, the reaction product of triamcinolone and acetophenone is named merely the acetophenone derivative of triamcinolone. By this of course is meant the product formed by splitting out the elements of water between the oxo group of the acetophenone and the 16,17- dihydroxy groups of triamcinolone. All temperatures given in the examples are in centigrade:

EXAMPLE 1 160a,] 7Ot- SOPI'OPYZidHE Triamcinolone (l6a,17u-Isopr0- pylia'ene 9a-Fluoro-A -Pregnadiene-l1B,16oc,1704,21- Tetr0l-3,20-Di0ne) To a suspension of 500 mg. of triamcinolone in 75 m1. of acetone is added 0.05 ml. of 72% perchloric acid and the mixture agitated at room temperature for three hours. During this period the crystals gradually dissolve and the clear solution is neutralized with dilute bicarbonate and the acetone removed in vacuo. The resulting crystalline suspension is filtered and the crystals washed with water. The dried material (about 523 mg.) melts at about 275- 278. Recrystallization from 95% alcohol gives the pure acetonide of the following properties: MP. about 288- 290; [a] +l09 (c., 0.75 in CHCl mgr-.2315 (e=16,100) x2353 2.94., 5.83, 5.99,. 6.17, 6.21,.

Analysis.-Calcd. for C H O F (434.49): C, 66.34; H, 7.19. Found: C, 65.95; H, 7.43.

This compound possesses about 20 times the activity of cortisone acetate in the rat liver glycogen assay and about 30 times the activity of cortisol in the cotton pellet anti infiarnmatory assay.

EXAMPLE 2 tion is worked up as described in Example 1 to give the pure acetonide having the same properties.

EXAMPLE 4 16a,17a-(2-Butylidene) T riamcinolone To a suspension of mg. of triamcinolone in 15 ml. of methylethylketone is added 0.05 ml. of 72% perchloric acid, and the mixture stirred at room temperature for two hours. The resulting solution is neutralized with sodium bicarbonate solution and after addition of water the meth- Analysis.Calcd. for C H O F (448.52): C, 66.94; H, 7.42. Found: C, 67.01; H, 7.41.

EXAMPLE 5 e,]7ot- (4-Methyl-2-Pentylidene) Triamcinolone )JWM 2.90, 5.83, 6. 629w.

max.

Analysis.-Calcd. for CzqHgqOsF (476.56): C, 68.04; H, 7.83. Found: C, 68.52; H, 7.93.

8 EXAMPLE 6 1 6 06,1 70L- (3 -Penty lz'dene) Triamcinolone A suspension of 200 mg. of triamcinolone in 30 ml. of diethylketone is treated for four hours as described Nuiol max.

11 in Example 5. The resulting isopentylidene derivative has the following properties: M.P. about 265286; [a] +91 (c., 0.69 in chloroform);

EXAMPLE 8 16a,17a-Ethylidene Triamcinolone To a suspension of 200 mg. triamcinolone in 15 ml. of freshly distilled paraldehyde is added 0.05 ml. of 72% perchloric acid and the mixture agitated for 3.5 hours at room temperature. The resulting solution is extracted with dilute bicarbonate and water, dried, and the excess paraldehyde removed in vacuo. The residual material represents 16a,17a-ethylidene triamcinolone.

Substitution of 9a-fluoro-A -pregnadiene-16a,17a-21. trial-3,11,20-trione for triamcinolone in the procedures of Examples 1 through 8, yield the corresponding ll-keto derivatives.

EXAMPLE 9 A suspensiono f 200 mg. of 9a-fluoro-A -pregnene-l1 3,- 16a,17a,21-tetrol-3,20-dione in 30 ml. of acetone is stirred at room temperature with 100 mg. of p-toluenesulfonic acid monohydrate for 18 hours. The clear solution is neutralized with sodium bicarbonate solution and the acetone evaporated in vacuo. The resulting crystals are filtered and dried in vacuo. Recrystallization from acetone-hexane gives the pure isopropylidene derivative of the following properties: M.P. about 270273; [-oz]' +l37 (c., 0.45 in chloroform);

A-nzzlysis.Ca1cd.: C H O F 4 3 6.50 0, 66.03; H, 7.62. Found: C, 66.03; H, 7.92.

Reaction of 9otfluoro-A -pregnene-l6a,17a,21-tiiol-3, 11,20-trione with acetone gives the corresponding ll-keto derivative.

EXAMPLE l 16a,17a-Cycl0hexylidene J6a-Hydroxyhydrocortis0ne Treatment of 16a-hydroxyprednisolone with acetone in the Ipresence of perchloric acid according to the procedure of Example 1 results in the formation of 160L,17a-i$0- propylidene 16a-hydroxyprednisolone.

EXAMPLE 12 -I6a,17a'(3--Pentylidene) 12a-Chl0ro-16a-Hydroxycortisone Treatment of 16m-hydroxy-12u-chlorocortisone with 'diethylketOne as described in Example 7 furnishes the 3'- pentylidene derivative of 16a-hydroxy-12a-ch1orocortisone.

EXAMPLE 13 1606,17OL'ISOP70PJ'I1616H8 1 6 a-H ya'roxy-J 2 a-Fluorohydrocortisone Treatment of l 6a-hydroxy-12a-fiuorohydrocortisone with acetone in the presence of perchloric acid as described in Example 1 yields the 16a,17a-isopropylidene derivative.

12 EXAMPLE 14 1611,] 7oL-Is0pr0pylidene IZa-Fluoro-I 6a-Hydr0xypredniso'lone Treatment of IZa-fluoro-l 6a-hydroxyprednisolone with acetone in the presence of perchloric acid as described in Example 1 yields the 16a,17a-isopropylidene derivative.

EXAMPLE 15 By applying the same sequence of reactions to 9a-fluor0- 115,166,17a-trihydroxyprogesterone the 16a,17a-isopropylidene derivative of 9u-flu0ro-A -pregnene-1l,8,16a,l7a-

' triol-3,20-dione can be prepared.

EXAMPLE 16 1 6 11,] 7 a-lsopropylidene 6a-Methyl-16a-Hydr0xyprednisolone Reaction of 6a-methyl-16a-hydroxyprednisolone with acetone as described in Example 1 yields the isopropylidene derivative of 6a-methyl-16a-hydr0xyprednisolone.

EXAMPLE 17 166a,] 7 ot-lsopropyl idene 6 Oc-M ethyl-9a-F luoro-l 60c- Hydroxy-Prednisolone Acetophenone Derivative of Triamcinolone To a suspension of 4 g. of triamcinolone in ml. of freshly redistilled acetophenone is added 1.0 ml. of 72% perchloric acid and the mixture stirred at room temperature for two hours, during which period all the triamcinolone has dissolved. The solution is neutralized by the addition of 8 ml. of 1.1 N NaOH and of suflicient aqueous bicarbonate to render it neutral. Water and chloroform is then added and the chloroformacetophenone layer concentrated in high vacuum. The residue is recrystallized from acetone-hexane and the crystals Washed well with hexane to remove adhering acetophenone. An analytical sample has the following properties: M.P. about 28l283 (dec.); [a] +23 (c., 0.98 in CHCI fig? 2.91, 5.80, 6.02, 6.16, 6.23, 13.06, 14.29,. Analysis.-Calcd. for C H O F (498.57): C, 69.93; H, 7.07. Found: C, 69.91; H, 7.04.

EXAMPLE 19 p-Nitroacetophenone Derivative of Triamcinolone To a suspension of 200 mg. of triamcinolone in a mixture of 7 ml. of dioxane and 4 grams of p-nitroacetophenone is added 0.05 ml. of 72% perchloric acid and the mixture stirred at room temperature for 3 /2 hours. The mixture is then neutralized with dilute sodium bicarbonate solution and the dioxane and excess p-nitroacetophenone removed by vacuum steam distillation. The residual aqueous suspension is extracted with chloroform,

t3 the chloroform layer Washed with water, dried over sodium sulfate and the solvent removed in vacuo. The remaining derivative is purified by recrystallization from acetone-hexane.

EXAMPLE 20 Acetophenone Derivative f 9a-Fluoro-M-Pregnene 1181611,] 711,21 -Tetr0l-3,20-Di0ne Benzaldehyde Derivative of 16a-Hydroxyhydroeortisone To a suspension of 100 mg. of 16ahydroxyhydrocorti acne in 15 ml. of benzaldehyde is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Example 18 and results in the formation of the benzaldehyde derivative of 16oc-hYdI'OXYhYdIOCOI'tiSOHB.

If 16a-hydroxycortisone is substituted for the 16e-hydroxyhydrocortisone in the procedure of Example 21 the benzaldehyde 16a-hydroxycortisone is obtained.

EXAMPLE 22 Furfaral Derivative 0 16a-Hydroxyprednisolone Treatment of 16a-hydroxyprednisolone with furfural in the presence of perchloric acid according to the procedure of Example 18 results in the formation of the furfural derivative of 16a-hydroxyprednisolone.

EMMPLE 23 Benzophenone Derivative 0 12oc-ChlOl0-160z- Hydroxycortisone Treatment of 16tx-hydroxy-12a-chlorocortisone with v benzophenone as described in Example 18 furnishes the benzophenone derivative of loa-hydroxy-12a-chlorocortisone.

EXAMPLE 24 Acetophenone Derivative of 16a-Hydr0xy-12oc- Fluorohydrocortisone Treatment of 16a hydroxy 120s fluorohydrocortisone with acetophenone in the presence of perchloric acid as described in Example 18 yields the acetophenone derivative.

EXAMPLE 25 Z-Acetylfuran Derivative of IZwFlLl0r0-16u- Hydroxyprednisolone Treatment of 12ot-fiuoro-16a'hydroxyprednisolone with 2-acetylfuran in the presence of perchloric acid as described in Example 18 yields the 2-acetyl-furan derivative.

EXAMPLE 26 P-Nilroacetopherione Derivative 0f IZa-Fluoro-A Pregneae-l1,8,16a,17a-Tri0l-3,20-Dione A solution of 30 mg. of l2a-fluoro-A -pregnene-115, 16a,17a-'tri0l3,20-di01'16 and 0.05 ml. of concentrated hydrochloric acid in ml. of dioxane and 100 mg. of p-nitroacetophenone is allowed to remain at room tem perature for 18 hours. The resulting mixture when worked up as described in Example 19 furnishes the pnitroacetophenone derivative.

By applying the same sequence of reactions to 9oc-fltl010- M-pregnene-l1{3,16a,17a-triol-3,20-dione the p-nitroacetophenone derivative of 9a-fluoro-A -pregnene-1153160;, l7a-triol-3,20-dione is prepared.

re. EXAMPLE 27 Acetophenone Derivative 0f 6a-Melhyl-16a- H ydroxyprednisolone Reaction of a-methyl-l6a-hydroxyprednisolone with acetophenone as described in Example 18 yields the acetophenone derivative of 6e-methyl-l6a-hydroxyprednisolone.

EXAMPLE 28 Acelopheaone Derivative of 9a-Fla0ro6a-Mezizyl- 16a-Hydroxyprednisolone Treatment of 9ot-fluoro-6a-methyl-1a-hydroxyprednisolone with acetophenone and perchloric acid as described in Example 18 furnishes the acetophenone derivative of the former.

In the same manner the acetophenone derivative of fiuoro-a-methyl-1a-hydroxyhydrocortisone can be prepared.

EXAMPLE 29 16st,] 7a-lsopropyiidene 90LFIl!0iO-Z 1fi,f6oc,17oc- Trillydroxyprogesierone To a suspension of 272 mg. of 9e-fluoro-A -pregnene- 11 ,8,l6a,17a-triol-3,20-dione in 38 ml. of acetone is added 0.025 ml. of 70% aqueous perchloric acid and the mix ture stirred at room temperature for 90 minutes. The mixture is neutralized with dilute sodium bicarbonate solution, the acetone evaporated in vacuo and the resulting suspension filtered. The dry precipitate is recrystallized from acetone-hexane and furnishes the pure acetonide of the following properties: MT. about 253255;

[rup e- (c., 0.35 in CHCI3);

re. 238 mu 6:17.400); taxi? 3. 5-86, M-

Analysis.Ca1cd. for C H O F: (420.50): C, 68.54; H, 7.91. Found: C, 68.72; H, 7.97.

This substance possesses three times the activity of cortisone acetate in the rat liver glycogen assay.

EXAMPLE 30 16:1,] 7a-1s0pr0pylidene 9a-Chl0ro-11fi,16a,17a- T rihydroxyprogesterone Following the procedure of Example 29 but substituting an equivalent amount of 9a-chloro-1lB.,16u,17e-trihydroxyprogesterone for the 9a-fluoro compound, there is obtained 16a,17a-isopropylidene 9a-chloro-11 ;8,16 x,17atrihydroxyprogesterone.

EXAMPLE 3i 16a,17a-Is0pr0pylidene 9a-Fluor0-A -Pregnerze-1611,17-

Dial-3,11,20-Tri0ne To a stirred solution of 50 mg. of 16a,17a-isopropylidene 90c fluoro A pregnene 11B,16a,l7a triol- 3,20-dione in 5 ml. of pure acetone is added dropwise 1.2 ml. of a solution of 200 mg. of chromic acid, 320 mg. of sulfuric acid and 1 ml. of Water in 9 ml. of acetone. After 30 minutes alcohol is added, the mixture diluted into water and the acetone removed in vacuo. Extraction of the suspension with chloroform and Washing of the chloroform extract with water followed by sodium 3 bicarbonate and drying over sodium sulfate yields after evaporation of the solvent the trione which is recrystallized from acetone-hexane.

EXAMPLE 32 16u,17u-Is0pr0pylidene 9a-C holoro-M-Pregnene-Z 6 01,] 7oz- Dial-3,11,20-Tri0ne Following the procedure of Example 31 but substituting an equivalent amount of 16a,17a-is0propylidene 9a chloro A pregnene 115,161,170: triol 3,20- dione for the 9oc-fit1010 compound, there is obtained 16cc,

EXAMPLE 33 1611,] 7a-Chl0ral Derivative of T riamcinolone To a suspension of 500 mg. of triamcinolone and 4 grams of chloral hydrate in 20 ml. of dioxane is added 0.1 ml. of 72% perchloric acid and the mixture agitated at room temperature for 24 hours. The mixture is filtered to remove some unreacted triamcinolone neutralized with sodium bicarbonate solution and extracted with chloroform. The chloroform dioxane extract is washed with water, dried over sodium sulfate and the solvents removed in vacuo. The residue represents the chloral derivative of triamcinolone.

EXAMPLE 34 T rz'flaoroacetonide of Triamcinolone To a suspension of 300 mg. of triamcinolone in 3 ml. of dioxane and 3 ml. of redistilled 1,1,1-trifiuoroacetone is added at 10 0.03 ml. of 72% perchloric acid. The reaction vessel is closed and the mixture agitated for 2 /2 hours at room temperature. At the end of this period the mixture is neutralized with dilute sodium bicarbonate solution and extracted with chloroform. The chloroform-dioxane extract is Washed with Water, dried over sodium sulfate and the solvents removed in vacuo. The residual crystalline material is recrystallized from acetone-hexane.

EXAMPLE 35 A suspension of 200 mg. of 9a-fluoro-A -pregnenel1,9, 16a,l7a,2l-tetrol-3,20-dione and 1.5 g. of chloral hydrate in 8 ml. of acetone is stirred at room temperature with 0.04 ml. of 72% perchloric acid for 18 hours. The clear solution is neutralized'with sodium bicarbonate solution and the chloral derivative isolated as described in Example 33.

Reaction of 9a-fluoro-A -pregnene-l6a,l7a-21-triol-3, 1 1,20-trione with chloral hydrate gives the corresponding ll-keto derivative.

EXAMPLE 36 1,1,1-Triflaroacetonide of 16a-Hydroxyhydroc0rtisone To a-suspension of 200 mg. of 16a-hydroxyhydrocortisome in 1 ml. dioxane and 1 ml. trifiuoroacetone is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Example 34 and results in the formation of the trifiuoroacetonide of 16-hydroxyhydrocortisone.

If l6a-hydroxycortisone is substituted for the 16mhydroxyhydrocortisone in the procedure of Example 36, 16a-hydroxycortisone .trifluoroacetonide is obtained.

EXAMPLE 37 H eptaflaorobutana'l Derivative of Triamcinolone To a'suspension of 100 mg. of triamcinolone in ml. heptafluorobutanal ethyl hemiacetal is added 0.05 ml. 72% perchloric acid, and the mixture stirred at room of of temperature for two hours. The resulting solution is neutralized with sodium bicarbonate solution and after addition of water, the excess reagent is evaporated in vacuo. The resulting crystals are filtered, washed with water and dried in vacuo.

EXAMPLE 38 I 6a-Hydroxyprednisolone 1,1,1-Triflu0roacet0nide Treatment of 16a-hydroxyprednisolone with 1,1,1-trifluoroacetone in the presence of perchloric acid according to the procedure of Example 33 results in the formation of l6a-hydroxyprednisolone 1,1,l-trifluoroacetonide.

EXAMPLE 39 16a,17a-Chl0ral Derivative of .72a-Chl0r0-l6a-Hydr0xycortisone Treatment of the 16a-hydroxy-l2a-chlorocortisone with chloral hydrate as described in Example 33 furnishes the chloral derivative of 16a-hydroxy-12a-chlorocortisone.

EXAMPLE 40 1606,170t-Chl0ll1l Derivative of 16a-Hydroxy-12a-Flu0rohydrocortisone Treatment of 16a-hydroxy-12a-fluorohydrocortisone with chloral hydrate in the presence of perchloric acid as described in Example 33 yields the l6a,l7a-chloral derivative.

EXAMPLE 41 160a,] 7a-C/1l0ral Derivative 0f 12a-Flu0r0-16a-Hydr0xyprednisolone Treatment of 12a-fluoro-l6a-hydroxyprednisolone with chloral hydrate in the presence of perchloric acid as described in Example 33 yields the 16a,17a-chloral derivative.

EXAMPLE 42 1 6a,] 7a-Ch loral Derivative of Z2aFlu0r0-A Pregrtene- 113,16a,]7a-Tri0l-3,20-Dione A solution of 30 mg. of l2a-fiuoro-A -pregnene-l1,8, 16a,17a-triol-3,20-dione, 200 mg. of chloral hydrate, and 0.05 ml. of 72% perchloric acid in 4 ml. of dioxane is allowed to remain at room temperature for 24 hours. The resulting mixture when worked up as described in Example 33 furnishes the chloral derivative.

By applying the same reaction to 9a-fiuoro-1l 3,l6a, 17a-trihydroxyprogesterone, the 16a,17a-chloral derivative of 9a-fluoro-A -pregnene-l 113,16a,17a-trio1-3,20-dione can be prepared.

EXAMPLE 43 6a-Methyl-16a-Hydr0xyprednisolone 1,1,1-Trifluor0- aceton'ide Reaction of 6a-methyl-1 6a-hydroxyprednis0lone with 1,1,l-trifluoroacetone as described in Example 33 yields the trifiuoroacetone derivative of 6a-methyl-16a-hydroxyprednisolone.

EXAMPLE 44 9oc-Flaoro-6a-Methyl-16a-Hydr0xyprednis0l0ne 1,1,1-

Trifluoroacetonide Treatment of 9a-fluoro-6a-methyl 16cc hydroxyprednisolone with 1,1,1-trifluoroacetone and perchloric acid as described in Example 33 furnishes the trifiuoroacetone derivative of the former.

In the same manner the trifiuoroacetone derivative of 9a-fluo-ro-6u-methylhydrocortisone can be prepared.

EXAMPLE 45 1 6w] 7ot-Isopropy lidene 9a-Methyl-A Pregnadiene- I1 9,]6 x,17a,21-Tetr0l-3,20-Di0ne To a suspension of 500 mg. of 16a-hydroxy-9a-methy1- prednisolone in ml. of acetone is added 0.05 ml. of 72% perchloric acid and the mixture agitated at room 17 temperature for three hours. During this period the crystals gradually dissolve and the clear solution is neutralized with dilute bicarbonate and the acetone removed in vacuo. The resulting crystalline suspension is filtered and the crystals washed with water.

EXAMPLE 46 16a,17a-Is0pr0pylidene 1 2a-Methyl-A -Pregnene-1 1B, 1604,] 711,21-Tetrl-3,20-Di0ne To a suspension of 500 mg. of l2a-methyl-l6a-hydroxyhydrocortisone in 75 ml. of acetone is added 0.05 of concentrated hydrochloric acid and the mixture is stirred at room temperature for 6 hours. It is then treated as described in Example 45 to give the pure product.

EXAMPLE 47 16a,17a-ls0pr0pylidene 1 Zea-1V1 ethyl-A -Pregnadiene 115,161,] 7a,21-Telr0l-3,20-Di0ne A suspension containing 100 mg. of 12OL-II16thyi-16LX- hydroxyprednisolone and 50 mg. of p-toluene-sulfonic acid in 15 ml. of acetone is stirred for 21 hours at room temperature. The clear solution is worked up as described in Example 45 to give the pure product.

EXAMPLE 48 EXAMPLE 49 To a suspension of 100 mg. of lZa-methyl-N-pregnene- 1106,1606,17ot-2ll@lIOl-3,20-dl0fl6 in 15 ml. of methylisobutylketone is added 0.05 ml. of 72% perchloric acid. The mixture is stirred at room temperature for 6 hours and the resulting solution extracted with dilute sodium bicarbonate solution, washed with water, the organic phase dried over sodium sulfate and the solvent evaporated in vacuo. Recrystallization of the resulting crystals from acetone-hexane gives the pure isohexylidene derivative.

EXAMPLE 50 A suspension of 200 mg. of 16a-hydroxy-9u-methylprednisolone in 15 ml. of redistilled cyclohexanone is treated for tWo hours as described in Example 49 to give the resulting cyclohexylidene derivative.

EXAMPLE 1 l 6a,17u- (3-Pentylidene) l2a-Methyl-A -Pregnadiene- 1 1,8,]6ot,1 704,21-Tetr0l-3,20-Di0ne A suspension of 200 mg. of l6ehydroxy-l2ot-methylprednisolone in 30 ml. of diethylketone is treated for four hours as described in Example 49 to give the isopentylidene derivative.

EXAMPLE 52 16a,17oc-Ethylidene 9a-Methyl-A -Pregnadiene-l1[3, 16s,] 7a,21Tetr0l-3,Z0-Di0ne To a suspension of 200 mg. 9a-methyl-16u-hydroxyprednisolone in 15 ml. of freshly distilled paraldehyde is added 0.05 ml. of 72% perchloric acid and the mixture agitated for 3.5 hours at room temperature. The resulting solution is extracted with dilute bicarbonate and water, dried, and the excess paraldehyde removed in vacuo. The residual material represents the l6a,17u-ethylidene derivative.

EXAMPLE 53 l6u,17ot-Chl0ral Derivative of 9ot-Methyl-d -Pregnene- 11,8,16a,17ot,21-Tetr0l-3,20-Di0ne To a suspension of 500 mg. of 9a-n1ethyl-A -pregnene- 11B,16u,17ot,2l-tetro1-3,20-dione and 4 grams of chloral hydrate in 20 ml. of dioxane is added 0.1 ml. of 72% perchloric acid and the mixture agitated at room temperature for 24 hours. The mixture is filtered to remove some unreacted steroid, neutralized with sodium bicarbonate solution and extracted with chloroform. The chlorofonn-dioxane extract is washed with water, dried over sodium sulfate and the solvents removed in vacuo. The residue represents the chloral derivative of 9u-methyl-16ot-hydroxyhydrocortisone.

EXAMPLE 54 1 6a,] 7a-Cycl0hexylidene 9 -Methyl-] 6 a-H ydroxyhydrocortisone To a suspension of mg. of 9ot-methyl-l6whydroxyhydrocortisone in 15 ml. of cyclohexanone is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Exanmple 49 and results in the formation of the cyclohexylidene derivative of 9u-methyl-16ot-hydroxyhydrocortisone.

If 9a-methyl-lowhydroxycortisone is substituted for the 9ct-methyl-l6whydroxyhydrocortisone in the pro cedure of Example 54, l6ot,l7a-cyclohexylidene 9a-methyl-loot-hydroxycortisone is obtained.

EXAMPLE 55 A solution of 30 mg. of IZa-methyl-M-pregnene-l1,8, 16oz,17ct-11'iOl-3,ZO-di0116 and 0.05 ml. of concentrated hydrochloric acid in 10 ml. of acetone is allowed to remain at room temperature for 18 hours. The resulting mixture when worked up as described in Example 45 furnishes the acetonide derivative.

By applying the same sequence of reactions to 9a-methyl-ll6,l6a,17a-trihydroxyprogesterone the l6tx,l7a-isopropylidene derivative of 9a-methyl-A -pregnened15,16a, 17a-trio1-3,20-dione can be prepared.

EXAMPLE 56 Acetophenone Derivative of 9a-Methyl-A -Pregnadiene 11fl,16a,17ot,21-Tetr0l-3,20-Di0ne To a suspension of 4 g. of l6a-hydroxy-9ot-methylprednisolone in 100 ml. of freshly redistilled acetophenone is added 1.0 ml. of 72% perchloric acid and the mixture stirred at room temperature for two hours, during which period all the triamcinolone has dissolved. The solution is neutralized by the addition of 8 ml. of 1.1 N NaOH and of sufficient aqueous bicarbonate to render it neutral. Water and chloroform is then added and the chlorofiorm-acetophenone layer concentrated in high vacuum. The residue is recrystallized from acetone-hexane and the crystals washed well with hexane to remove adhering acetophenone to yield the pure acetophenone derivative.

EXAMPLE 57 Acetophenone Derivative of 9a-llletltyl-l6a-Hydroxyprednisolone 21 Acetate EXAMPLE 58 Acetophenone Derivative of 9ot-Methyl-A -Pregnene JI/3,]6oi,1 7 u,21 -Tetrl-3,20-Di0ne A suspension of 200 mg. of 9a-methyl-A -pregnene-11,6, 16a,17a,21-tetrol-3,20-dione in 30 ml. of acetophenone is stirred at room temperature with 100 mg. of p-toluenesulfonic acid monohydrate for 18 hours. The clear solution is neutralized with sodium bicarbonate solution and the acetone evaporated in vacuo. The resulting crystals are filtered and dried in vacuo. Recrystallization from acetone-hexane gives the pure acetophenone derivative.

Reaction of 9a-methyl-A -pregnene,16a,17a,21-trio1-3, 11,20-trione with acetophenone gives the corresponding 11-keto derivatives.

EXAMPLE 59 Benzaldehyde Derivative of 9a-Methyl-16oc- H ydroxyhydrocortisone EXAMPLE 60 Furfaral Derivative of 12a-Methyl-16a- Hydroxyprednisolone Treatment of 12u-methyl-16a-hydroxyprednisolone with furfural in the presence of perchloric acid according to the procedure of Example 56 results in the formation of the furfural derivative of IZa-methyl-l6a-hydroxyprednisolone.

EXAMPLE 61 Benzophenone Derivative of 12a-Methyl-16a- H ydroxycortisone Treatment of 16a-hydroxy-12a-methylcortisone with benzophenone as described in Example 56 furnishes the benzophenone derivative of 16a-hydroxy-12a-methylcortisone.

EXAMPLE 62 2-Acetylfuran Derivative of 12a-Methyl-16a- Hydroxyprednisolone Treatment of 12a-methyl-16a-hydroxyprednisolone with Z-acetylfuran in the presence of perchloric acid as described in Example 56 yields the Z-acetylfuran derivative.

EXAMPLE 63 Ethyl Levulinate Derivative of T riamcl'nolone To a suspension of 400 mg. of triamcinolone in ml. of redistilled ethyl levulinate is added 0.05 ml. of 72% perchloric acid and the mixture stirred at room temperature for one hour and minutes, complete dissolution of triamcinolone occurring after 50 minutes. The mixture is neutralized with dilute sodium bicarbonate solution and distributed between chloroform and water. The chloroform layer is Washed with Water, dried over sodium sulfate and concentrated in high vacuum to remove chloroform and excess ethyl levulinate. The crystalline residue after purification by crystallization from acetone-hexane has the following properties: M.P. about 196-198; [a] (c., 1.11 in CHCI AnalySia-Calcd. for C H O F (520.57): C, 64.59; H, 7.16. Found: C, 64.54; H, 7.15.

By substituting ethyl acetoacetate or ethyl pyruvate for the ethyl levulinate in Example 63, the corresponding derivatives are formed.

EXAMPLE 64 Levalinic Acid Derivative of Triamcinolone To a solution of 200 mg. of the ethyl levulinate derivative of triamcinolone in 24 ml. of methanol, which has been evacuated several times and kept under nitrogen is added 1 ml. of oxygen-free 10% potassium carbonate solution. The solution is allowed to remain at room temperature for 24 hours, after which time it is acidified with dilute sulfuric acid. Water is added and the methanol removed in vacuo. The resulting suspension is extracted with chloroform and the chloroform extract Washed with three 2 ml. portions of sodium bicarbonate solution. The sodium bicarbonate extract containing the levulinic acid derivative is acidified with dilute sulfuric acid and extracted with chloroform. The chloroform extract is dried over sodium sulfate and the solvent removed in vacuo. The residual crystalline material after recrystallization from methanol has the following properties: M.P. about 240-242 (dec.); [0c] +51 (c., 0.56 in CHCl M53; 2.38 ma (e=15,500); A253? 2.85, 2.95, 3.00, 5.75

Analysis.-Calcd. for C H O FH O (510.54): C, 61.15; H, 7.12. Found: C, 61.23; H, 7.12.

Similarly, by substituting the ethyl acetoacetate and ethyl pyruvate derivatives of triamcinolone for the ethyl levulinate derivative in the procedure of Example 64, the acetoacetic acid and pyruvic acid derivatives of triamcinolone are formed, respectively.

EXAMPLE 65 Sodium Levulinate Derivative of T riam'cinolone EXAMPLE 66 Methyl Glyoxylate Derivative of T riamcinolone Following the procedure of Example 63, but substitut ing methyl glyoxylate for the ethyl levulinate, there is obtained the methylglyoxylate derivative of triamcinolone.

Substitution of 9a-fluoro-A -pregnadiene-16a,17a,21- triol-3,11,20-trione for triamcinolone in the procedures of Examples 63 through 66 yield the corresponding ll-keto derivatives.

EXAMPLE 67 Following the procedure of Example 63 but substituting 400 mg. of 9a-fiuoro-A -pregnened1B,16a,17a,21-tetrol-3, 20-dione for the triamcinolone, there is obtained the ethyl levulinate derivative of a-fiuoro-A -pregnene-11,6,1604, 17a,21-tetrol-3,20-dione.

Reaction of 9a-fluoro-'A -pregnene-16a,17u,21-triol-3, 11,20-trione with ethyl levulinate gives the corresponding ll-keto derivatives.

21 EXAMPLE 68 Ethyl Acetoacetate Derivative of 16ot-Hydr0xyhydrocortisone EXAMPLE 69 Ethyl Levttlinate Derivative of Ida-Hydroxyprednisolone Treatment of 16a-hydroxyprednisolone with ethyl levulinate in the presence of perchloric acid according to the procedure of Example 63 results in the formation of the ethyl levulinate derivative 16e-hydroxyprednisolone.

EXAMPLE 70 Ethyl Levulinate Derivative of 12oz-Cl'll070-16oc- Hydroxycortisorze Treatment of the 16ot-hydroxy-l2oc-chlorocortisone with ethyl levulinate as described in Example 63 furnishes the ethyl levulinate derivative of 16CL-hYClIOXY-l20t-Chl0l'0- cortisone.

EXAMPLE 71 Ethyl Levulinate Derivative f16u-Hydr0xy-l2a- Fl LIOVOIIYdIOCOIII SOIZC Treatment of 16a hYdIOXY-lZa fluorohydrocortisone with ethyl levulinate in the presence of perchloric acid as described in Example 63 yields the ethyl levulinate derivative.

EXAMPLE 7.2

Ethyl Levulirtate Derivative of 12a-Flu0r0-16a- H ydroxy preanisolotte Treatment of l2e-fluoro-16et-hydroxyprednisolone with ethyl levulinate in the presence of perchloric acid as described in Example 63 yields the ethyl levulinate derivative.

EXAMPLE 73 Ethyl Pyruvate Derivative 0f 1 2oc-Flltor0-A -Pleglte116- 1iB,16e,1 7a-Tri0l-3,20-Di0rie EXAMPLE 74 Ethyl Levulinate Derivative 0f 6a-Metlzyl-16a- H ydroxy prednisolone Reaction of 6a-methyl-16e-hydroxyprednisolone with ethyl levulinate as described in Example 63 yields the ethyl levulinate derivative of 6ot-methyl-l6ct-hydroxyprednisolone.

EXAMPLE 75 Ethyl Levuliriate Derivative 0 9ot-F l u0r0-6 u-M ethyl-1 6 ol- Hy droxy prednisol one Treatment of 9a-fluoro-6e-methyl-16ot-hydroxyprednisolone with ethyl levulinate and perchloric acid as described in Example 63 furnishes the ethyl levulinate derivative of the former.

In the same manner the ethyl levulinate derivative of 22 9a-fluoro-6a-methyl-l6ot-hydroxyhydrocortisone can be prepared.

The following examples are illustrative of the preparation of these compounds of this invention wherein an ester is present in the 21-position (Z is halogen or acyloxy). All temperatures given in the examples are in centigrade:

EXAMPLE 76 ]6a,17a-Is0pr0pylidene Triamcinolorte 21-A cetate A solution of 50 mg. of triamcinolone acetonide in 1 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetonehexane gives pure acetate of the following properties: M.P. about 266; [a] -f-92 (c., 0.59 in CHClg);

M53; 238 mu (e=l6,100); 3.01, 5.71, 5.79, 6.016.0-i,

Aimlysis.Calcd. for: C H O F (476.52): C, 65.52; H, 6.98. Found: C, 65.49; H, 6.81.

EXAMPLE 77 Acetophenone Derivative of Triamcirtolone 21-Acetate N iol Mix.

A solution of 50 mg. of the acetophenone derivative of triamcinolone in 1 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetonehexane gives the pure acetate.

EXAMPLE 78 1 6 [1,1 7e-Chl0ral Derivative of Triamcinolone 21 -M0n0acetate A solution of 570 mg. of 160t,l706-Chl01fi1 derivative of triamcinolone in 10 ml. of anhydrous pyridine and 20 ml. of acetic anhydride is allowed to remain at room temperature for 18 hours. The reagents are removed in vacuo, the dried residue dissolved in 40 ml. of benzene and chromatographed on 12 grams of acid-washed alumina. Elution with 1 1. each of benzene, 5% chloroform in benzene, and 10% chloroform in benzene yields the pure chloral derivative of triamcinolone 21-monoacetate of the following properties: MP. about 281-284 (dec); [a] +36 (c., 1.0 in CHCl A33 237 m (e=19,800); x3135 2.85, 3.00, 5.69, 5.78,

EXAMPLE 79 16e,17a-Chl0ral Derivative of Triamcinolone 21- Hemisuccinic Acid A solution of 500 mg. of the 160L,17Ct-Glll0131 derivative i of tri-amcin-olone and 1 gram of succinic anhydride in 5 ml. of anhydrous pyridine is heated at 60-70" for 2 hours. After cooling to 15 2 grams of ice is added and the mixture poured slowly with stirring onto 20 ml. of crushed ice containing 2 ml. of concentrated sulfuric acid. The resulting precipitate of the 16,17-chloral derivative of triarncinolone 21-hemisuccinic acid is filtered and washed well with water until free from sulfuric acid. The dried material is crystallized from 25% alcohol.

EXAMPLE 16 7u-Chl0ral Derivative of 9u-Methyl-A -Pregnene- 11fl,16oc,1 70:,21 -Tetr0l-3,2O-Di0ne 2] -Acetate 23 zene, chloroform in benzene, and chloroform in benzene yields the pure chloral derivative of 9ot-methyl- M-pregnened1[3,16a,17u,21tetro1-3 ,20-dione 21-acetate.

EXAMPLE 81 A solution of 50 mg. of 12a-methyl-16a-hydroxydrocortisone 16a,17a-acetonide in 1 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane gives the pure acetate.

EXAMPLE 82 Ethyl Levulinate Acid Derivative of Triamcinolone 21 -Acetate A solution of 5 0 mg. of the ethyl levulinate derivative of triamcinolone in 1 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane yields the pure acetate.

EXAMPLE 83 Triamcinolone Acetonide ZJ-Sodz'um Hemisuccinate (a) Preparation of triamcinolone acetonide 21-hemisuccinic acid: A solution of 4 g. of triamcinolone 16a,170c-21C6t011id6 and 8 g. of succinic anhydride in 40 ml. of anhydrous pyridine is heated at 6070 for 2 hours. After cooling to 20 g. of ice is added and the mixture poured slowly with stirring onto 150 ml. of crushed ice, containing 16 ml. of concentrated sulfuric acid. The resulting precipitate of triamcinolone acetonide 21-succinic acid is filtered and washed well with Water until free from sulfuric acid. The dried material (about 4.5 g.) is crystallized from 95% alcohol with the aid of carbon which yields the pure acid of the following properties: M.P. about 23l-233 [a] +93 (c., 0.39 in CHCl Nuiol 294 5,71, 519, 6.02, 6.17, 6.26#

(b) Preparation of triamcinolone acetonide 21-sodium hemisuccinate: 500 mg. of triamcinolone acetonide 21- hemisuccinic acid is dissolved in a minimum of 95% alcohol and the resulting solution is neutralized with 0.1 N sodium hydroxide solution. The neutralized solution is freed from alcohol in vacuo, extracted with chloroform to remove residual unneutralized acid and the aqueous solution lyophilized in high vacuum. The residual white powder represents the pure sodium salt.

16a-I7a-(2'-Butylidene) T riamcinolone 21-S0dium Hem isuccz'nate Following the procedure of Example 83, but substituting 4 g. of 16a,17a-(2-butylidene)triamcinolone for the triamcinolone acetonide, there is obtained 16ot,17a-(2'- butylidene)triamcinolone 21-sodium hemisuccinate.

EXAMPLE 86 IZot-FhmrO-J 6 Ot-H ydroxyprednz'solone Acetonide 2]- Sodium Hemisuccinaze Following the procedure of Example 83, but substituting 4 g. of IZa-fluoro-l6ot-hydroxyprednisolone acetonide for the triamcinolone acetonide, there is obtained 120:-

. '24 fiuoro 16cc hydroxyprednisolone acetonide 21-sodium hemisuccinate.

EXAMPLE 87 16%] 7 ot-Erhylia'ene T rz'amcinolone 21-S0dium H emisuccinate Following the procedure of Example 83, but substituting 4 g. of 16a,17a-ethylidene triamcinolone for the triamcinolone acetonide, there is obtained 16a,17a-ethylidene triamcinolone 21-sodium hemisuccinate.

Similarly, l6a,l7a-cyclohexylidene triamcinolone, 16a,17a-(3 -pentylidene) triamcinolone, 9a-fluoro-16ot-hydroxyhydrocortisone acetonide,

' 16u-hydroxyprednisolone acetonide,

12ot-fluoro-16a-hydroxyhydrocortisone acetonide,

l2a-chloro-1ot-hydroxyprednisolone acetonide,

6a-methyl-16ot-hydroxyprednisolone acetonide,

and 9ot-fiuoro-6tx-methyl-16m-hydroxyprednisolone acetonide yield their respective 21-sodium hemisuccinate derivatives.

EXAMPLE 88 Triamcinolone Acetophenone ZJ-Sodium Hemisuccinalte Following the procedure of Example 83, but substituting 4 g. of triamcinolone acetophenone for the triamcinolone acetonide, there is obtained triamcinolone acetophenone 21-sodium hemisuccinate.

Similarly, the acetophenone derivative of 9a-fluOrO-16ozhydroxyhydrocortisone 16a,17a-benzylidene 16ot-hydroxyhydrocortisone, 16,17 furfurylidene l6a-hydroxyprednisclone, the benzophenone derivative of 12u-chlor0-16ahydroxycortisone, the acetophenone derivative of 160:- hydroxy-IZa-fiuorohydrocortisone, 16a,17a acetylfurylidene IZoc-fluoro 16oz hydroxyprednisolone, the acetophenone derivative of 6ot-methy'l-16a-hydroxyprednisolone, the acetophenone derivative of 9d-flllOIO-60t-m6thyl- 16a-hydroxyprednisolone, and the p-nitroacetophenone derivative of triamcinolone yield the corresponding 21- sodium hemisuccinate derivative.

EXAMPLE 89 Traimcinolone Acelonide ZI-Potassium Hemiglutarate EXAMPLE 90 Triamcinolone Acezonide ZJ-Mesylaze To a solution of l g. of triamcinolone acetonide in 10 ml. of anhydrous pyridine is added at 0 1 ml. of methanesulfonyl chloride. After two hours at 0 ice water is added and the precipitated mesylate is removed by filtration. The precipitate is washed thoroughly with water and dried in vacuo, and recrystallized from acetonehexane. The pure mesylate has the following properties: M.P. about 248250 (dec.) or 286287 (dec.) (polymorphic forms); [a] +92 (c., 1.12 in CHCl Analysis-Calcd. for C H O SF (498.55); C, 57.81; H, 6.27; F, 3.81; S, 6.43. Found: C, 57.87; H, 6.20; F, 3.83; S, 6.33.

Similarly, by substituting aryl sulfonyl chlorides or other lower alkanesulfonyl chlorides for the methane sulfonyl chloride in the procedure of Example 90, the corresponding 21-arylsulfonyloxy and 21-alkanesulfonyloxy derivatives are formed. Thus, p-toluenesulfonyl chloride, ethanesulfonyl chloride and propanesul-fonyl chloride yield triamcinolone acetonide 21- -toluenesulfonate, triamcinolone acetonide 21-ethanesulfonate and triamcinolone acetonide 2l-propanesulfonate, respectively.

25 EXAMPLE 91 1 6 oc-H ydrxy-9crF l uorohydrocortisone A cetonide 21 M esy late To a solution of 1.5 g. of 16oc-hydroxy-9a-fluorohydrocortisone acetonide in ml. of dry pyridine is added at 0, 1.5 ml. of methanesulfonyl chloride. After standing in the refrigerator for 2 /2 hours, excess methanesulfonyl chloride is destroyed by the addition of a small amount of ice, after which ice-water is added slowly to precipitate the reaction product. After /2 hour in the refrigerator the material is filtered off, Washed thoroughly with water and dried in vacuo. The resulting crude material after recrystallization from acetone-hexane gives the pure 21-mesylate of the following properties: M.P. about 225227 (.dec.); [oc] +112 (c., 0.5 in chlf.);

A231? 2.86; 2.94; 5.76; 5.90; 5.06; 6.14 Analysis.-Calcd. for C H O FS (500.56): C, 58.35; H, 6.85; S, 6.23. Found: C, 58.18; H, 6.82; S, 6.05.

Similarly, but substituting other 160c,17oc-8C6t318 or ketals for the triamcinolone acetonide in Example 90 or the 9ot-fiuoro-16a-hydroxyhydrocortisone acetonide. in Example 91, the corresponding Zl-mesylates are formed. Thus, the acetophenone derivatives of triamcinolone,

the acetophenone derivative of 9or-fiuoro-l6a-hydroxyhydrocortisone, 16a,17a-benzylidene-16whydroxyhydrocortisone, 16 a, 17 a-furfurylidene-l 6 a-hydroxyprednisolone,

the benzophenone derivative of 120t-Ch10lO-16Ct-hydl'OX cortisone, the acetophenone derivative of 16a-hydroxy-12a-fluorohydrocortisone, 16a,17a-2-acetylfurylidene-12u-fiuoro-16ot-hyclroxyprednisol one,

the acetophenone derivative of 6a-methy1-16tt-hydroxyprednisolone, the acetophenone derivative of 9m-fluoro- 6a-methyl-16ot-hydroxyprednisolone and the p-nitracetophenone derivative of triarncinolone yield their respective 21-mesylate derivatives.

EXAMPLE 92 A solution of 500 mg. of triamcinolone acetonide 21- mesylate and 1.5 g. of sodium iodide in 15 ml. of acetone is refluxed for hours. The reaction mixture is then diluted with water and the crystals filtered off and dried in vacuo. After recrystallization from acetone-hexane, pure 21-iodo-2l-desoxytriamcinolone acetonide has the following properties: MI. about l76-178 (dec.); [a] 1l3 (c.,1.12inChCl Almlysis.-Calcd. for C I-1 0 1 1 (544.40) C, 52.94; H, 5.55; I, 23.31. Found: C, 52.31; H, 6.02; 1, 22.69.

EXAMPLE 93 A solution of 250 mg. of 9a-fluor0-16a-hydroxyhydrocortisone 16a.,17 x-acetonide 21-mesylate and 750 mg. of sodium iodide in 7 ml. of acetone is refluxed for 40 hours, the resulting reaction mixture diluted with water and the resulting crystals filtered, washed Well with water and dried in vacuo. Recrystallization of the crude product from acetonehexane furnishes the pure iodo compound possessing the following properties: MP. about 173-175 (dec.); [a] +l3O (c., 0.52 in chloroform);

Similarly, but substituting the 21-mesylates of other 16u,17or-acetals or ketals for the triamcinolone acetonide 21-mesylate in Example 92 or the 9oc-fluoro-16a-hydroxy hydrocortisone acetonide 21-mesylate in Example 93, the corresponding 21-iodo derivatives are formed.

EXAMPLE 94 Nuiol 02 5J8 603, 6.20, 6.20;.

Arwlyss.Calcd. for (1 1-1 0 5 (436.48); C, 66.04; H, 6.93; F, 8.59. Found: C, 65.64; H, 6.93; F, 7.81.

This compound possesses about 29 times the activity of cortisone in the rat liver glycogen assay and about 20 times the activity of hydrocortisone in the rat anti-inflammatory assay.

Nuiol max.

EXAMPLE 95 A solution of 200 mg. of triamcinolone acetonide 21- mesylate and 9 00 mg. of lithium chloride in 25 ml. of dimethyl formamide is kept at for 24 hours. The mixture is poured on ice, extracted with chloroform and the choloroforrn extract washed with water and dried over sodium sulfate. Evaporation of the solvent in vacuo furnishes the crystalline chloride, which after recrystallization from acetone-ethanol has the following properties: M.P. about 310.

Anaiysis.-Calcd. for C H O FCI (454.96): C, 63.35; H, 7.09; Cl, 7.99. Found: C, 63.31; H, 6.83; Cl, 7.92.

When the lithium chloride in the above reaction is replaced by lithium bromide and the reaction is shortened to 12 hours there is obtained the corresponding 2l-brorno derivative.

Similarly, by substituting the 2l-mesyla'tes of the acetophenone derivative of triamcinolone,

the acetophenone derivatives of 9u-tluoro-l6oc-hydroxyhydrocortisone, 16a.,17o -benzylidene 16a-hydroxyhydrocortisoue,

the benzophenone derivative of l2a-chloro-l6a hydroxycortisone, the acetophenone derivative of la-hydroxy- EXAMPLE 96 Bis-(Triamcinolone J6a,I7a-Acet0nide) 21,21-Sulfi2e To a solution of 200 mg. of triamcinolone 16a,17otacetonide in 6 ml. of anhydrous pyridine is added at -15 with stirring 0.2 m1. of thionyl chloride. The reaction is allowed to proceed for 2 /2 minutes at -15 after which time ice water is added. The mixture is taken up in chloroform and the resulting chloroform extract washed with water, 1 N sulfuric acid, water, dilute sodium bicarbonate and again with water. The solution is dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue (about 200 mg.) is dissolved in 20 ml. of warm chloroform and chrom atographed on 4 g. of neutral alumina. Chloroform (100 ml.) elutes about 120 mg. of crystalline material, which after recrystallization from acetone furnishes about 80 mg. of the pure 2l,2l-sulfite derivative having the following properties: M.P. about 285286 (dec.); [111 +1l4 (c., 0.53 in chloroform);

Nuiol mm 2.91, 5.80, 6.04, 6.19, 6.22 (shoulder), and 8.30

Analysis.-Calcd. for C H O F S (915.02): C, 63.00; H, 6.61; S, 3.50. Found: C, 62.71; H, 6.72; S, 3.80.

EXAMPLE 97 Bis- T riamcinolone 160a,] 70c-A cetonide) 21,21 Carbonate To a solution of 200 mg. of triamcinolone 16a,17aacetonide in 6 ml. of anhydrous pyridine is added at with stirring 2.5 ml. of a 10% solution of phosgene in toluene. The reaction is allowed to run at 0 for minutes, after which time ice water is added. The resulting mixture is extracted with chloroform and the chloroform extract washed with water, 1 N sulfuric acid, water, dilute sodium bicarbonate and again with water. After drying with sodium sulfate the chloroform extract is evaporated to dryness in vacuo and the residual crystals (about 240 mg.) recrystallized from chlorform-95% ethanol. About 80 mg. of crystalline material is obtained posessing the following properties: M.P. greater than 340;

2.87, 2.95, 5.65, 5.76, 6.02, 6.16 and 6.22

Analysis.C-alcd. for: C H O F (894.97): C, 65.75; H, 6.75; F, 3.87. Found: C, 65.85; H, 6.85; F, 3.96.

EXAMPLE 98 Bis-(Triamcinolone 16a,17a-Acet0nide) 21 ,2] -Sulfate By substituting an equivalent amount of sulfuryl chloride for the thionyl chloride in the procedure of Example 96, bis-(triamcinolone 160:,17oc-E1C6t0nid6) 31,21-sulfate is obtained.

EXAMPLE 99 as. cortisone l6st,l7a-acetonide for the triamcinolone acetonide, bis-(9a-fluoro-l6a-hydroxyhydrocortisone :,1711- acetonide)21,2l'-sulfite is obtained.

EXAMPLE 101 Potassium Salt of T riamcinolone 1604,17oz-AC6l0ilid6-21- Phosphate To a mixture of 3 ml. of anhydrous pyridine and 0.15 ml. of phosphorous oxychloride maintained at 15 is added dropwise over a ten minute period a solution of 200 mg. of triamcinolone l6a,17aacetonide in 3 ml. of pyridine. The resulting solution is allowed to remain at -15 for an additional 20 minutes at which time 0.2 ml. of water is added and the mixture is allowed to warm up to room temperature. One hour after the addition of water, the solution is concentrated in vacuo to about 2 ml. diluted with 10 ml. of water, extracted with chloroform and adjusted to a pH of 6.8 with potassium carbonate solution. The neutralized solution is lyophilized, triturated with alcohol and the alcoholic solution concentrated to small volume. The potassium salt of triamcinolone acetonide 21-phosphate crytsallizes under these conditions.

This invention may be variously otherwise embodied Within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of the 16,17-cyclic ketals of ketones and 16,17-cyclic acetals of aldehydes of at least two carbon atoms and steroids of the 16a,17a-dil1ydroxy-3,ZO-diketo-M-pregnene series containing a substituent selected from the group consisting of fl-hydroxy and keto in the ll-position.

2. 16,17-cyclic ketals of a steroid of the 9a-fluoro-l Iii, 160:,17a-trihydroxy-A -pregnene series.

3. 16,17-cyclic acetals of a steroid of the 9a-fluoro-11p, 16a,l7a-trihydroxy-A -pregnene series and aldehydes of at least two carbon atoms.

4. 16,17-cyclic ketals of a steroid of the 9oc-flIlOIO-11B, 16a, 1 7a-trihydroXy-A -pregnadiene series.

5. 16,17-cyclic acetals of a steroid of the 9a-fluoro-11B, 16a,l7a-trihydroXy-A -pregnadiene series and aldehydes of at least two carbon atoms.

6. A compound selected from the group consisting of steroids of the general formula and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein R is hydrogen, R is fi-hydroxy, and together R and R is keto; X is selected from the group consisting of hydrogen, halogen, and lower alkyl, at least one X being hydrogen; Y and Y are each selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of hydrogen, halogen, hydroxy and acyloxy; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboXy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monoyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heretocyclic.

7. 16a,17a-lower alkylidene 9a-halo-l6a-hydroxyprednisolone, wherein the alkylidene radical contains at least two carbon atoms.

8. 16a,l7a-isopropy1idene 9a-fiuoro-l6a-hydroxyprednisolone.

9. l6a,17a-lower alkylidene 9u-halo-l6a-hydroxyhydrocortisone, wherein the alkylidene radical contains at least two carbon atoms.

10. l6 x,l7a-lower alkylidene l2rx-halo-l6u-hydroxyhydrocortisone wherein the alkylidene radical contains at least two carbon atoms.

11. 16oc,17a10Wer alkylidene l2a-halo-l6whydroxyprednisolone, wherein the alkylidene radical contains at least two carbon atoms.

12. 16cz,17ec-1OW61' alkylidene 12a-halo-A -pregnene 11B,16oc,l7oL-t1i01-3,20-di0118, wherein the alkylidene radical contains at least two carbon atoms.

13. 16a,17aphenyl-lower alkylidene 9oc-halO-l6oc-hydroxyprednisolone.

14. Triamcinolone acetophenonide.

l5. 16u,l7a-lower alkylidene 9a-halo-11B,l6u,l7a-trihydroxyprogesterone, wherein the alkylidene radical contains at least two carbon atoms.

16. 1600,17oc-1OW61 alkylidene 9a-halo-A -pregnene-l6a, 17a-diol,3,ll,20-trione, wherein the alkylidene radical contains at least two carbon atoms.

17. The 16,17-ketal derivative of 9a-halo-l6rx-hydroxyprednisolone and an X0 lower alkanoic acid ester.

18. The 16,17-ketal derivative levulinic acid.

19. The 16,17-ketal derivative of 9a-halo-l6a-hydroxyhydrocortisone and an oxo lower alkanoic acid ester.

20. 16a,17u-1ower alkylidene 9ot-halo-l6oc-hyclroxyprednisolone 21-(lower alkanedioic acid), wherein the alkylidene radical contains at least two carbon atoms.

21. Triamcinolone acetonide 2l-hemisuccinic acid.

22. An alkali metal salt of 1606,1704-1OW6I alkylidene 9a-halo-l6a-hydroxyprednisolone 2l-(lower alkanedioic acid), wherein the alkylidene radical contains at least two carbon atoms.

23. T riamcinolone acetonide 2l-sodium hemisuccmate.

24. 16a,17oc-10W6r alkylidene 9a-halo-l6rx-hydroxyprednisolone 2l-(lower alkane)sulfonate, wherein the alkylidene radical contains at least two carbon atoms.

25. 16a,l7 x-lower alkylidene 9a,2l-dihalo-A -pregnadieIlB-l1B,160L,17OLllI'lOl-3,20-dl0n6, wherein the alkylidene radical contains at least two carbon atoms.

26. 16a,l7 x-lower alkylidene 9ot-(lower alkyl)-l6ot-hydroxyprednisolone, wherein the alkylidene radical contains at least two carbon atoms.

27. 16a,17a-lower alkylidene l2a-(lower alkyl)-16u-hydroxyprednisolone, wherein the alkylidene radical contains at least two carbon atoms.

28. l6u,l7u-lower alkylidene 9u-(lower alkyD-la-hydroxyhydrocortisone, wherein the alkylidene radical contains at least two carbon atoms.

29. 16oc,17a-1OW1' alkylidene 12a-(lower alkyl)-l6uhydroxyhydrocortisone, wherein the alkylidene radical contains at least two carbon atoms.

30. BiS-(16a,17a-l0Wer alkylidene 9a halo-l6a-hydroxyprednisolone) 2l,21-sulfite, wherein the alkylidene radical contains at least two carbon atoms.

31. Bis(l6a,l7ot-lower alkylidene 9u-halo-l6u-hydroxyprednisolone) 2l,2l-carbonate, wherein the alkylidene radical contains two carbon atoms.

32. A process for increasing the physiological activity of steroids which comprises reacting a steroid of the 160:, 17a-dihydroxy-3,ZO-diketo-M-pregnene series containing a substituent selected from the group consisting of [3- hydroxy and keto in the ll-position with a compound selected from the group consisting of aldehydes of at least two carbon atoms and ketones.

of triamcinolone and 30 33. A process for preparing a compound selected from the group consisting of steroids of the general formula and the l,2-dehydro and 6,7-dehydro derivatives thereof, wherein R is hydrogen, R is selected from the group consisting of a-hydroxy, B-hydroxy and a-acyloxy, and together R and R is keto; each X is selected from the group consisting of hydrogen, halogen, and lower alkyl, at least one X being hydrogen; Y and Y' are each selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of hydrogen, halogen and hydroxy; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic, which comprises interacting a corresponding compound selected from the group consisting of steroids of the general formula I EH 2 X o 1 R -QH H --0E .1 and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein R, R, X, Y, Y and Z are as above defined, with a compound of the general formula I CH Z and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein R is hydrogen, R is selected from the group consisting of hydroxy and a-acyloxy, and together R and R is keto; each X is selected from the group consisting of hydrogen, halogen, and lower alkyl, at least one X being hydrogen; Y and Y are each selected from the group I Y I and the 1,2-dehydro and 6,7-dehydro derivatives thereof,

wherein R, R, X, Y, Y and Z are as above defined, with a compound of the general formula:

wherein n, A and B are as above defined, in the presence of an acid catalyst, and recovering the resultant steroid.

35. An alkali metal salt of l6a,l7a-lower alkylidene triamcinolone 21-ph0sphate.

32 36. A steroid of the formula wherein X is halo and Q is halo lower alkyl.

37. A steroid of the formula wherein X is halo and Q is halo lower alkyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,584,271 Huffman Feb. 5, 1952 2,726,240 Moffctt Dec. 6, 1955 2,736,732 Knowles Feb. 28, 1956 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,048,581 August 7, 1962 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 28, lines 35, 37, 40 and 42, after "trihydroxy", each occurrence, insert 3,20-diketo Signed and sealed this 8th day of March 1966.

[SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER testing Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE 16,17 CYCLIC KETALS OF KETONES AND 16,17-CYCLIC ACETALS OF ALDEHYDRES OF AT LEAST TWO CARBON ATOMS, AND STEROIDS OF THE 16A, 17A-DIHYDROXY-3,20-DIKETO*4 PREGNENE SERIES CONTAINING A SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF B-HYDROXY AND KETO IN THE 11-POSITION. 